Sulindac disposition when given once and twice daily

Area of Science:

• Pharmacokinetics
• Drug Metabolism
• Chronopharmacology

Background:

• Sulindac is commonly prescribed twice daily.
• The efficacy of once-daily evening dosing for maintaining therapeutic sulindac metabolite levels is not well-established.
• Understanding drug metabolite pharmacokinetics is crucial for optimizing dosing regimens.

Purpose of the Study:

• To compare the pharmacokinetic profile of sulindac's active sulfide metabolite.
• To determine if once-daily evening sulindac dosing is equivalent to twice-daily dosing in sustaining plasma metabolite concentrations.
• To investigate the influence of circadian rhythms on sulindac metabolite levels.

Main Methods:

• A randomized crossover study involving 12 healthy subjects.
• Administration of sulindac 200 mg twice daily (9 A.M. and 9 P.M.) versus 400 mg once daily (9 P.M.) for 7 days each.
• Measurement of plasma concentrations of the sulfide metabolite at steady state.

Main Results:

• Once-daily evening sulindac dosing resulted in a significantly greater area under the plasma concentration-time curve (AUC) for the sulfide metabolite compared to twice-daily dosing.
• Mean trough concentrations of the sulfide metabolite did not differ significantly between the two dosing regimens.
• A circadian rhythm in metabolite accumulation was observed, with higher levels during the 9 A.M. to 9 P.M. period during twice-daily dosing.

Conclusions:

• Once-daily evening sulindac dosing appears to be as effective, if not more so, than twice-daily dosing in sustaining plasma sulfide levels.
• Diurnal variations in metabolite accumulation, potentially influenced by circadian rhythms, play a role in sulindac pharmacokinetics.
• Further clinical studies are warranted to evaluate the therapeutic efficacy of once-daily evening sulindac administration.